Activation of cerebellar climbing fibers increases cerebellar blood flow: role of glutamate receptors, nitric oxide, and cGMP.
BACKGROUND
The mechanisms regulating the cerebellar microcirculation during neural activity are poorly understood. One of the major neural inputs to the cerebellar cortex is the climbing fiber (CF), a pathway that uses excitatory amino acids, including glutamate, as a transmitter. We studied whether CF activation increases cerebellar blood flow (BFcrb) and, if so, we investigated the role of glutamate receptors, nitric oxide (NO) and cGMP, in the response.


METHODS
The CF were activated by harmaline administration (40 mg/kg, i.p.) in halothane-anesthetized rats with a cranial window placed over the cerebellar vermis. BFcrb was monitored by a laser-Doppler probe, and arterial pressure and blood gases were controlled.


RESULTS
With Ringer superfusion, harmaline produced sustained increases in BFcrb that peaked 20 minutes after administration (+115 +/- 13%; n=6; P<.05). The increases in BFcrb were substantially reduced by superfusion with tetrodotoxin (10 micromol/L; -91 +/- 5%; n=5; P<.05 from Ringer). The response was also attenuated by the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor inhibitor 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)-quinoxaline (100 micromol/L; -70 +/- 6%; P<.05; n=5), but not by the N-methyl-D-aspartate receptor blocker 2-amino-5-phosphonopentanoic acid (500 micromol/L; P>.05; n=5). The response was attenuated by the nonselective NO synthase (NOS) inhibitor nitro-L-arginine (1 mmol/L; -73 +/- 5%; n=6) or by 7-NI (50 mg, i.p.; -71 +/- 5%; n=5), a relatively selective neuronal NOS inhibitor. The soluble guanylyl cyclase inhibitor 1H-1,2,4oxadiazolo[4,3-a]quinoxalin-1-one (100 micromol/L) attenuated the response to harmaline (-73 +/- 5; P<.05; n=6) but not to superfusion with adenosine (P>.05; n=5) or 8-bromo-cGMP (P>.05; n=5).


CONCLUSIONS
Activation of the CF system increases BFcrb. The response depends on activation of glutamate receptors and is in large part mediated by NO via stimulation of soluble guanylyl cyclase. Glutamate receptors NO and cGMP are important factors in the mechanisms of functional hyperemia in cerebellar cortex.
Yang
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G
Department of Neurology, University of Minnesota Medical School, Minneapolis 55455, USA.
Iadecola
C
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002245:Carbon Dioxide / Q000097:blood; D002531:Cerebellum / Q000098:blood supply* / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006246:Harmaline / Q000494:pharmacology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D017470:Receptors, Glutamate / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine; D013779:Tetrodotoxin / Q000494:pharmacology; D017585:Ultrasonography, Doppler, Transcranial
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D002245:Carbon Dioxide; D019335:Nitroarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D018698:Glutamic Acid; D013779:Tetrodotoxin; D015763:2-Amino-5-phosphonovalerate; D026423:S-Nitroso-N-Acetylpenicillamine; D006246:Harmaline; D010396:Penicillamine; D006152:Cyclic GMP; D010100:Oxygen